Campbell’s Chapter 29 Neoplasms of the Testis Brent Zamzow D.O.

Introduction Most common malignancy in males 15-35 Survival <50% prior to 1970 >95% in 1997 Improved survival: Accurate tumor markers Effective chemo Modifications of surgical technique Mostly radiosensitive Backup treatments if primary treatments fail

WHO Classification of Testicular Tumors Germ Cell Tumors Precursor lesions-intratubular malignant germ cells (carcinoma in situ) Tumors of one histologic type (pure forms)   Seminoma     Variant-seminoma with syncytiotrophoblastic cells   Spermatocytic seminoma     Variant-spermatocytic seminoma with sarcoma  Embryonal carcinoma   Yolk sac tumor   Polyembryoma   Trophoblastic tumors     Choriocarcinoma     Choriocarcinoma with other cell types    Placental site trophoblastic tumor   Teratoma     Mature teratoma     Dermoid cyst     Immature teratoma     Teratoma with malignant areas Tumors of more than one histologic type (mixed forms)-specify types and estimate percentage Sex Cord/Gonadal Stromal Tumors Pure forms  Leydig's cell tumor   Sertoli's cell tumor     Large-cell calcifying Sertoli's cell tumor     Lipid-rich Sertoli's cell tumor Granulosa cell tumor  Adult-type granulosa cell tumor   Juvenile-type granulosa cell tumor Tumors of thecoma/fibroma group Incompletely differentiated sex cord/gonadal stromal tumors Mixed forms Unclassified Forms Tumors Containing Both Germ Cell and Sex Cord/Gonadal Stromal Elements Gonadoblastoma Mixed germ cell-sex cord/gonadal stromal tumors, unclassified Miscellaneous Tumors Carcinoid tumor Tumors of ovarian epithelial types Lymphoid and Hematopoietic Tumors Lymphoma Plasmacytoma Leukemia Tumors of Collecting Ducts and Rete Adenoma Carcinoma Tumors of the Tunica, Epididymis, Spermatic Cord, Supporting Structures, and Appendices Adenomatoid tumor Mesothelioma   Benign   Malignant Melanotic neuroectodermal Desmoplastic small round cell tumor Soft Tissue TumorsUnclassified TumorsSecondary TumorsTumor-like Lesions Nodules of immature tubules Testicular lesions of adrenogenital syndrome Testicular lesions of androgen-insensitivity syndrome Nodular precocious maturation Specific orchitis Nonspecific orchitis Granulomatous orchitis Malakoplakia Adrenal cortical rest Fibromatous peritonitis FuniculitisResidue of meconium peritonitis Sperm granuloma Vasitis nodosa Sclerosing lipogranuloma Gonadal splenic fusion Mesonephric remnants Endometriosis Epidermal cyst Cystic dysplasia Mesolithial cyst Others

Classification Germ Cell Tumors (GCT) >50% GCT are mixed Seminoma Classic or Typical Anaplastic Spermatocytic Nonseminoma Embryonal Cell Carcinoma Yolk Sac Tumor Teratoma Choriocarcinoma >50% GCT are mixed

Normal testis Sertoli cells straight arrow, leydig cells curved arrow

Classic Seminoma 82-85% of seminomas Mostly men in 30’s Rarely occurs in adolescents or infants Clear cytoplasm, dense nucleus Synctiotrophoblasts in 10-15% Elevated B-HCG in 10% hCG up to 500 ng/mL Lymphocytes in 20%

Classic Seminoma Lymphocytes, fried egg apperance

Anaplastic Seminoma 5-10% of seminomas Greater mitotic activity Higher rate of local invasion Increased rate of metastasis Higher rate of B-HCG production Stage for stage – treatment outcomes same as classic seminoma Classification no longer used Only higher metastatic potential

Anaplastic Seminoma Pleomorphism, hyperchromasia

Spermatocytic Seminoma 3 sizes of cells 9% of seminomas 50% older than 50 Very low metastatic potential Prognosis favorable Orchiectomy only

Spermatocytic Seminoma

Seminoma Painless testicular mass Testis size normal or smaller in 15% Age 35-55 classic seminoma Peak 35-39 >60 spermatocytic seminoma Most common germ cell tumor in men >65 Rare before 10

Nonseminomatous Germ Cell Tumors (NSGCTs) Embryonal Choriocarcinoma Teratoma Yolk Sac Mixed

Embryonal Carcinoma Small, hard, irregular mass Age 25-35 Smallest germ cell tumor 40% <2cm Invades tunica vaginalis Often close to rete testis Gray/white with necrosis or hemorrhage Highly malignant

Embryonal Overlapping nuclei, anaplastic cells, pappilary projections

Embryonal Tumor Markers Can have elevated hCG & AFP Synctiotrophoblasts common in stroma hCG not elevated in pure embryonal AFP usually due to yolk sac elements

Choriocarcinoma Commonly present metastatic Usually a peripheral mass Central hemorrhage Must have synctiotrophoblasts & cytotrophoblasts 1-2% of tumors hCG elevated in >99% Age 20-30 Worst prognosis

Choriocarcinoma C-cytotrophoblasts, arrow-syncytiotrophoblasts

Teratoma Derived from ectoderm, mesoderm, endoderm 2 or more embryonic germ cell layers in various stages of maturation Can contain bone, cartilage, intestinal, pancreatic, liver, muscle, neural cells Lined by any cell type Large, lobulated, nonhomogeneous Rarely can get malignant teratoma Histologically benign

Teratoma respiratory epithelium – arrowheads , curved arrow bone (mesoderm), straight arrows – mucin producing glands (endoderm)

Teratoma Classifications 3% of adult, 38% of children Mature Immature With malignant transformation Simple epidermoid cysts 3% of adult, 38% of children Elevated AFP 20-25% Age 25-35 Epidermoid cysts – benign Metastatic teratoma resistant to chemo & radiation

Yolk Sac Tumor Other names Most common testis tumor age 0-10 Endodermal Sinus Tumor Adenocarcinoma of the infantile testis Juvenile Embryonal Carcinoma Orchioblastoma Most common testis tumor age 0-10 Slow growing mass 25% have hydrocele AFP elevated in >90% In adult mixed tumors, 1/3 have yolk sac elements

Yolk Sac Tumor Yellow, mucinous Higher incidence of hematogenous spread Treatment >80% confined to testis & cured by radical orchiectomy Low-volume retroperitoneal lymph node involvement – RPLND Advanced disease – chemo Residual mass unresponsive to chemo – radiation Survival 87% for all stages

Yolk sac Arrows = AFP reaction

Mixed Tumors 60% of tumors Most frequent mixed tumor Embryonal, seminoma, yolk sac, teratoma & syncytiotrophoblasts Document % of volume for each type AFP & hCG can be elevated Age 10-30 Managed as NSGCT

Intratubular Germ Cell Neoplasia: CIS of Testis Precursor to all GCTs except spermatocytic seminoma Risk Factors Contralateral testis w/ unilateral ca (2-38%) Cryptorchidism (5-6%) Infertility (1%) Extragonadal GCT (35-50%) Intersex (25-100%) Evenly distributed through testis Open biopsy is reliable US unreliable Treatment Options Observation – treatment of choice Orchiectomy Radiation (European treatment) Chemo ineffective Treatment depends on age, b/l or unilateral, atrophy, physician’s philosophy. Progression may take 15 years. Some may screen intersex or other high risk

Epidemiology of GCTs Incidence Laterality Lifetime risk white male – 1 in 500 1/3 risk for American blacks Highest incidence – Scandinavia, Switzerland, Germany, New Zealand Lowest incidence – Asia, Africa Laterality 2-3% are bilateral More common on R Cryptorchidism more common on R

Etiology Cryptorchidism 7-10% of tumors had cryptorchidism 1940 – 48x higher risk 1980 – 3-14x higher risk 5-10% cryptorchidism make tumor in other side Structural abnormalities seen in cryptorchid testis at 3 years Orchiopexy does not prevent cancer, allows clinical surveillance Trauma not causative, just makes you go to doctor. Hormones – estrogen exposure DES,

Pathogenesis Tunica albuginea – barrier to spread ½ of NSGCT present as metastatic Complete spontaneous regressions rare Consider all adult GCT malignant Infantile teratoma is benign Lymphatic mets is common in all GCTs Choriocarcinoma – lymph & vascular

Patterns of Spread Predictable (except for choriocarcinoma) Spermatic cord has 4-8 lymph channels Right-sided tumors Interaortocaval at level of L2 body Can cross from R to L Left-sided tumors Para-aortic between L ureter, L renal vein, aorta, origin of IMA NSGCT – doubling time 10-30 days 85% of those who die from GCT, die within 2yrs of orchiectomy

Presentation Signs & symptoms Usually painless lump 30-40% c/o heaviness or dull ache 10% acute pain 10% present with metastatic manifestations Neck mass, cough, nausea, vomiting, lumbar pain, bone pain Gynecomastia is present in 5% of GCTs Any hypoechoic area on US w/i tunica suspicious for tumor Gynecomastia is systemic endocrine manifestation – hCG, prolactin, estrogen, androgens, still undefined relationship.

Staging Based on pathology of primary tumor & imaging of chest & retroperitoneum Understage 20% (Stage I undergoing RPLND) 10-15% have undetectable nodal mets 5-10% relapse at extranodal sites

Staging Systems American Joint Committee on Cancer (AJCC) – 1997, 2002 TNMS system Stage grouping Stage 0, Ia, Ib, Is, IIa, IIb, IIc, III Stage I No nodes, no mets Stage II Positive regional nodes Stage III Nonregional nodes or pulmonary mets

Imaging CXR CT MRI – no benefit PET Scan – no benefit over CT PA & lateral CXR should be initial radiologic procedures CT Abdominal CT is best test to look for retroperitoneal mets Do after orchiectomy If CXR or abdominal CT is abnormal, get chest CT MRI – no benefit PET Scan – no benefit over CT Cannot detect microscopic disease

Tumor Markers Draw tumor markers prior to orchiectomy Alpha-fetoprotein (AFP) Serum protein of early embryo Human Chorionic Gonadotropin (hCG) Secreted by placenta Lactic Acid Dehydrogenase (LDH) Placental Alkaline Phosphatase (PLAP) & Gamma-Glutamyl-Transpeptidase (GGTP) Low sensitivity

AFP Early levels 5-7 day half life Can be elevated in: In fetus produced by fetal yolk sac, liver, GI tract Highest levels at 12-14 weeks gestation At 1 year declines to low adult levels 5-7 day half life Can be elevated in: Testis, liver, pancreas, stomach, lung ca Normal pregnancy Benign liver disease Ataxia-telangiectasia Tyrosinemia Never elevated in pure choriocarcinoma or seminoma Pure embryonal Teratocarcinoma Yolk sac Combined

HCG Has alpha & beta subunits Alpha subunit similar to FSH, LH, TSH Beta subunit is distinct Secreted by placenta to maintain corpus luteum Syncytiotrophoblastic cells produce hCG in GCTs 24-36 hour half life Elevated in all choriocarcinoma, 40-60% of embryonal, 5-10% of seminomas Can be elevated in: Marijuana smokers Liver, pancreas, stomach, lung, breast, kidney, bladder ca Elevated LH - false positive HCG LH may cross react with HCG assays causing false positive

LDH High levels in muscle, liver, kidney, brain High false positive rate Most useful as a marker for bulky disease

Tumor Markers NSGCTs Be careful Elevated AFP 50-70% Elevated hCG 40-60% Elevated either or both 90% 10% of advanced disease will have normal tumor markers Be careful Elevated AFP can be from liver dysfunction Elevated hCG can be from hypogonadism & marijuana Normal markers does not mean no residual disease 10-20% after chemo & RPLND for bulky disease have viable tumor despite normal markers Degree of AFP or hCG elevation is proportional to tumor burden

Treatment of GCTs Radical orchiectomy for local control Offer sperm banking prior to surgery >50% have mets, so most require further treatment Treat retroperitoneal lymph nodes Large retroperitoneal mets – chemo initially 65-85% seminomas confined to testis 60-70% nonseminomas present as recognizable metastatic disease

Partial Orchiectomy Option for Careful frozen sections Organ confined tumor <2cm Especially incidentally found, nonpalpable Solitary testis or w/ B/L tumors Careful frozen sections Can use crushed ice, gentle occlusion of spermatic cord

Stage I Seminoma 15-25% staging error Radiation – treatment of choice 20-25 Gy to para-aortic nodes 5-year disease free survival >95% Long-term side effects Infertility, GI, 2nd malignancy 3% relapse (outside retroperitoneum) & need chemo Chemotherapy Carboplatin x1-2 experimental Surveillance Optimum surveillance protocol unknown Give option for <6cm, no vascular invasion, normal hCG, compliant, <34 15-20% will relapse & require XRT or chemo Stage I = no nodes, survival is same with surveillance & XRT, surveillance more common due to increased risk of secondary malignancy

Stage IIa & IIb Seminoma XRT Ipslilateral external iliac, b/l common iliac, paracaval, para-aortic, cisterna chyli Avoid kidney Shield contralateral testis 5-yr disease free survival 80% 3% relapse Chemo If nodes close to kidney Stage 2a&b, retroperitoneal nodes <5cm

Stage IIc & III Seminoma Before platinum – radiation Cisplatin-based chemo now treatment of choice Bleomycin, Etoposide, Cisplatin (BEP) x3–4 Etoposide, Cisplatin (EP) x4 90% complete response to chemo at 4yrs 10% relapse after initial chemo response Postchemo residual retroperitoneal mass Well-delineated, >3cm – resect Mass = GCT, then salvage chemo (vinblastine, ifosfamide, cisplatin) Otherwise observation IIC node >5cm, III is nonregional node or pulmonary mets, response numbers are all over the place

NSGCTs Low Stage High Stage Surveillance Chemo RPLND Good vs. Poor risk

RPLND 1948 Retroperitoneal nodes are first & sometimes only areas of mets Gold Standard of staging Modified template RPLND Most likely areas to be involved Minimize side effects Infertility, ejaculatory dysfunction

Stage I NSGCTs Radiation - not used in North America, relapse rate 24% Surveillance Option for low risk: No vascular/lymphatic invasion (<T2) <40% embryonal Motivated, reliable pts Relapse 28%, survival 99% Protocol CXR, tumor markers q1mo x1yr, q2mo x1yr, q3-6mo up to 10 more yrs CT q2-3mo x2yrs, q6mo up to 10yrs Chemo – BEP x2-3 Option for low or high risk: T2 or higher (vascular/lymphatic invasion) >40% embryonal Modified template RPLND If negative, then observe 70% of RPLNDs find no disease If <2cm nodes (N1), observe or adjuvant chemo – BEP x2 or EP x2 If >2cm nodes (N2), adjuvant chemo – BEP x2 or EP x2 5-10% relapse outside field of RPLND staging is inaccurate in at least 25% & only way to accurately stage is RPLND

Stage IIa & IIb NSGCTs Bilateral RPLND Chemo – BEP x3 or EP x4 N1 (nodes <2cm) – observe or adjuvant chemo – BEP x2 N2 (nodes 2-5cm) – adjuvant chemo – BEP x2 Chemo – BEP x3 or EP x4 If post-orchiectomy tumor markers elevated If nodes >3cm Stage IIa&b – nodes <2, 2-5cm

Stage IIc & III NSGCTs Low Risk No nonpulmonary visceral mets AFP <1000, hCG <5000, and LDH <1.5x normal Intermediate Risk Markers between low & high risk High Risk Nonpulmonary visceral mets AFP >10,000, hCG >50,000, or LDH >10x normal Chemo tailored to this classification

Stage IIc & III NSGCTs Low risk High risk Chemo – BEP x3 or EP x4 92% 5-yr survival High risk Chemo – BEP x4 or B/isosfamide/P 48% 5-yr survival

Stage IIc & III NSGCTs After Chemo Complete response (normal tumor markers, no residual mass) Observe 10% relapse & need salvage chemo Partial response (normal tumor markers, residual mass) Full B/L RPLND & resect residual mass 10-20% GCT – salvage chemo 40-50% teratoma – observe or resect 40% necrosis – observe Poor response (elevated tumor markers or no shrinkage of mass) Salvage chemo, high dose chemo & autologous bone marrow transplant 25% long term survival Growing teratoma syndrome, can transform into sarcoma or adenocarcinoma. If partial response, can omit RPLND if >90% response & no teratoma in primary tumor.

Chemo & XRT Toxicity 2nd Malignancy Bleomycin Etoposide Cisplatin Up to 18% 25yrs after XRT Chemo Higher long-term incidence of leukemia, melanoma, lymphoma, colon, stomach, kidney, prostate, bladder, thyroid, rectum, pancreas, connective tissue cancers Bleomycin Pulmonary Toxicity Etoposide Myelosuppression Cisplatin Nephrotoxicity – also Carboplatin Low Magnesium Neurotoxicity & Ototoxicity

Other Testicular Tumors Extragonadal Germ Cell Tumors Mediastinum, retroperitoneum, sacroccygeal region, pineal gland Leydig Cell Tumor Sertoli Cell Tumor Gonadoblastoma Lymphoma

Leydig Cell Tumors 1-3% of testicular tumors 10% malignant Average survival – 3 years if malignant Reinke’s crystals – red extracellular lobular crystals Presentation Precocious puberty in kids Elevated testosterone, urinary 17-ketosteroids Mass Impotence, gynecomastia Treatment Radical orchiectomy & surveillance Endocrine w/u

Leydig Cell Tumor

Sertoli’s Cell Tumors <1% testicular tumors Most common testicular tumor in dogs 10% malignant Any age Radical orchiectomy RPLND if metastatic

Others Gonadoblastoma Epidermoid Cyst Rete Testis Adenocarcinoma 0.5% testicular tumors 80% are in phenotypically female pts Good prognosis Epidermoid Cyst 1% testicular tumors ? Monolayer teratoma Benign Rete Testis Adenocarcinoma Age 20-80 Very malignant Adrenal Rest Tumor B/L tumor, CAH – remission w/ corticoid treatment Lymphoma 5% testicular tumors Most common secondary tumor Most common testicular tumor in age >50 ½ are B/L

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